Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders

ABSTRACT

The invention provides compounds effective as sphingosine-1-phosphate receptor modulators for treatment of cardiopulmonary diseases, such as hypertension (including malignant hypertension), angina, myocardial infarction, cardiac arrhythmias, congestive heart failure, coronary heart disease, atherosclerosis, angina pectoris, dysrhythmias, cardiomyothopy (including hypertropic cardiomyothopy), heart failure, cardiac arrest, bronchitis, asthma, chronic obstructive pulmonary disease, cystic fibrosis, croup, emphysema, pleurisy, pulmonary fibrosis, pneumonia, pulmonary embolus, pulmonary hypertension, mesothelioma, ventricular conduction abnormalities, complete heart block, adult respiratory distress syndrome, sepsis syndrome, idiopathic pulmonary fibrosis, scleroderma, systemic sclerosis, retroperitoneal fibrosis, prevention of keloid formation, or cirrhosis.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the priority of U.S. provisional applicationSer. No. 62/056,946, filed Sep. 29, 2014, the disclosure of which isincorporated by reference herein in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under MH084512, awardedby the National Institutes of Health. The government has certain rightsin the invention.

BACKGROUND

Antagonism of the subtype 3 of the sphingosine-1-phosphate receptors(S1PRs) is proposed to have therapeutic utility in asthma, chronicobstructive pulmonary diseases, as well as additional therapeuticutilities based upon receptor expression and the effects ofpharmacological antagonism of gene deletion. Five high affinityG-protein coupled receptors for sphingosine 1-phosphate (S1P) areidentified (1) and the crystal structure of S1PR₁ has been solved (2).This cluster of receptors is medically important because thenon-selective S1PR agonist fingolimod is an effective oral therapy forthe treatment of relapsing-remitting multiple sclerosis by alteringlymphocyte function. Various S1P receptor subtypes that differ inspatial distribution, coupling and function can singly or incombination, play complex roles in embryonic formation of the arterialmedia, blood pressure regulation and cardiac function. FTY720(fingolimod) in man is associated with significant sinus bradycardia,heart block and a prolongation of QTc interval (3, 4). Atropine reversalof the sinus bradycardia (5) and the demonstration of sinus bradycardiawith S1PR₁-selective agonists in man (6) as well as rodents (7)suggested that sino-atrial (SA) node effects and those events resultingfrom alterations in ventricular conduction are distinctly regulated.Mice deficient in S1PR₃ are resistant to a variety of pharmacologicaleffects produced by agonists of S1PR₃ including pulmonary and cardiacfibrosis (8-10), cardiac arrhythmias (11) as well as being resistant tocomplex pathologies such as cytokine storm and sepsis syndrome.

Sepsis syndrome, a consequence of infection and characterized by a stateof uncontrolled systemic inflammation, kills approximately 200,000people per year in the US (12, 13). According to global estimates, theincidence of sepsis is believed to range from 140-240 cases per 100,000,with fatality rates as high as 30%. If associated with circulatorycollapse and end-organ failures, fatality rates remain in 50-80% range(14, 15). The 1979-2000 epidemiologic sepsis study estimated a 17billion annual cost of sepsis care in the US (16), a value that islikely to be higher today due to the increased cost of healthcare.Although early intervention and modern supportive care practices insepsis have slightly increased in overall sepsis survival rates, to 37to 30% (17-21), there is still an obvious unmet medical need thatrequires development of new therapeutic strategies to combat thishealthcare burden.

Despite measures to alter pathogen burden, and intensive supportivecare, sepsis syndrome has high morbidity, mortality and a significantcost burden, reflecting imbalance between pro-inflammatory cytokines andelements of inflammation essential for host protection (22). Recent workdefining the signature for key elements regulating systemicinflammation, has defined new, chemically tractable targets fortherapeutic intervention that are genetically validated in animalmodels. Our recent work has demonstrated that blunting not abolishinghost responses and cytokine storm provides important protection fromimmunopathology while sparing antiviral immune responses (23-25). Inbacterial infections we have now demonstrated by both genetic deletionof receptor (26), as well as with the use of early selective, neutralantagonists, that S1P signaling via S1PR₃ on dendritic cells (DC)exacerbates systemic inflammation and lethality in stringent models ofsepsis, i.e. both LPS-induced inflammation and in cecal ligationpuncture (CLP) models.

Sepsis syndrome is a significant unmet medical need, as no effectivetreatment options exist beyond antimicrobial therapies and supportiveintensive care. Behind this medical challenge lie multiple, complexpathological endpoints that coalesce in final common pathways ofend-organ failure, and prospective identification of patient subsets isa work in progress. None-the-less, the importance of the unmet medicalneed, coupled with new mechanistic insights into shared criticalpathways, offers new opportunities for mechanism-based interventions.Characteristic pathological symptoms of severe sepsis include profoundinflammation, dysregulated coagulation, tissue microvascular edema,cardiovascular collapse, renal dysfunction and ultimately death. Anadditional long-term consequence is pulmonary fibrosis. These symptomsresult primarily from the hyper-activation of the host's immune systemreacting to the pathogen's invasion (27, 28). Understanding thefactor(s) regulating the onset and progression of the host's immuneoveractivation is relevant for designing novel effective therapies forsepsis. Multiple lines of evidence support crucial roles for S1PRs inthe control of immune cell trafficking and cardiovascular functions inphysiology and disease (29, 30). S1P, a circulating bioactivelysophospholipid derived from the ceramide pathway binds to andactivates five closely related G-protein coupled receptors, referred toas S1PR₁₋₅. Interestingly, human diseases with an active inflammatorycomponent, such as multiple sclerosis (MS), coronary atherosclerosis,and lupus, have elevated plasma or local S1P levels (31-34). In the caseof sepsis, there is even plasma elevation of a major S1P carrierlipoprotein, Apoprotein M, in disease subjects, and is now a risk factorfor poor prognosis (35, 36). Thus it is likely that S1P signaling toneis consequently altered in septicemia. Since discontinuation of Xigris(37), an intended target of the endothelial components of sepsis, andsince immunosuppressive corticosteroidal therapy can be controversialdue to adrenal insufficiency occurring in sepsis (38, 39), there is alimited arsenal to combat sepsis. Inhibiting, with a systemic selectivesmall molecule antagonist, S1PR₃ on DCs, on vascular smooth muscle,coronary artery smooth muscle and bronchial smooth muscle can contributeto improving the therapeutic outcome in multiple clinical syndromescharacterized by bronchoconstriction, pulmonary fibrosis, coronaryartery constriction, cytokine amplification by dendritic cells, as wellas the generation of disseminated intravascular coagulopathy, based upondata showing that S1PR₃ signaling contributes to pro-inflammatorysignals, fibrosis and to poor sepsis outcome.

Previous findings indicated that S1PR₃ deficient DCs (taken from S1PR₃knockouts), significantly enhanced the survival of mice administeredwith a 90% lethal dose (LD90) of LPS or in mice following the CecalLigation Puncture (CLP) model of polymicrobial sepsis (26). Mostimportantly, the study pointed out that treatment with AUY954, aselective S1P₁ agonist that sequesters B- and T-lymphocytes from theblood (40), and is useful for dampening inflammation in animal models oflocalized inflammation (41), did not infer any protection in the samestudy. Another report using similar transfer methods has just shown thatS1PR₃-deficiency in DCs significantly blunted pro-inflammatory mediatorsin renal ischemia/reperfusion studies and lowered kidney immunopathologyin mice (42). Interesting, the authors further implicated IL-4 signalingas a downstream mediator of the S1PR₃ deficiency benefits in renalischemia/reperfusion. Furthermore, siRNA knockdown of S1PR₃ in bonemarrow derived DCs (BMDC) greatly reduced transwell DC migration, andmigration to the mesenteric lymph node (43), suggesting that S1PR₃ isdirectly involved in DC migration. Overall, the available evidencestrongly suggests that down-modulating S1PR₃ DC signaling, as proposedwith a systemic S1PR₃ antagonist, may open a new therapeutic opportunityin sepsis syndrome. These data strongly suggest that an S1PR₃ antagonistmay be valuable during the early management period of sepsis care,characterized as the critical therapeutic window with potential forboosting survival (44) (45).

SUMMARY

The invention provides, in various embodiments, a compound of formula(I)

wherein each of Ar¹, Ar², and Ar³ is independently selected (C6-C10)arylring system or a (5- to 10-membered) heteroaryl ring system, wherein anyaryl or heteroaryl ring system of Ar¹, Ar², or Ar³ is optionally fusedwith a cycloalkyl or a heterocyclyl ring;

wherein any aryl or heteroaryl of Ar¹, Ar², or Ar³ is each optionallyindependently mono- or multi-substituted with up to three substituentsselected from the group consisting of (C1-C4)alkyl, (C2-C4)alkenyl,halo, halo(C1-C4)alkyl, OH, monohydroxy(C1-C4)alkyl,dihydroxy(C2-C4)alkyl, monohydroxy(C1-C4)alkoxy, dihydroxy(C2-C4)alkoxy,(C1-C4)alkoxy, (C2-C6)acyl, (C1-C6)alkoxycarbonyl(CH₂)₀₋₂,carboxy(CH₂)₀₋₂, oxo, cyano, NR₂(CH₂)₀₋₂, NR₂C(═O)(CH₂)₀₋₂,NR₂C(═O)(CH₂)₀₋₂O(CH₂)₀₋₂, (C1-C4)C(═O)N(R), (C1-C4)OC(═O)N(R), C═NOR,(C3-C10)cycloalkyl, (5- to 10-membered)heterocyclyl, (C6-C10)aryl, and(5- to 10-membered) heteroaryl; wherein any cycloalkyl, heterocyclyl,aryl or heteroaryl substituent of Ar¹, Ar², or Ar³ is itself optionallysubstituted with up to three secondary substituents selected from thegroup consisting of (C1-C4)alkyl, (C2-C4)alkenyl, halo,halo(C1-C4)alkyl, OH, monohydroxy(C1-C4)alkyl, dihydroxy(C2-C4)alkyl,monohydroxy(C1-C4)alkoxy, dihydroxy(C2-C4)alkoxy, (C1-C4)alkoxy,(C2-C6)acyl, (C1-C6)alkoxycarbonyl(CH₂)₀₋₂, carboxy(CH₂)₀₋₂, oxo, cyano,NR₂(CH₂)₀₋₂, NR₂C(═O)(CH₂)₀₋₂, NR₂C(═O)(CH₂)₀₋₂O(CH₂)₀₋₂,(C1-C4)C(═O)N(R), (C1-C4)OC(═O)N(R), and C═NOR;

each R is independently H, (C1-C4)alkyl, hydroxy(C2-C4)alkyl, cyano, or((C1-C4)alkyl-O)₁₋₂(C1-C4)alkyl, or two R groups together with an atomto which they are both joined can form a ring;

each R′ is independently H, (C1-C4)alkyl, hydroxy(C2-C4)alkyl,(CH₂)₀₋₂C(═O)O(C1-C4)alkyl, or (C3-C6)cycloalkyl;

X is a bond, (CH₂)₁₋₂, (CH₂)₀₋₂N(R)(CH₂)₀₋₂, (CH₂)₀₋₂O(CH₂)₀₋₂,(CH₂)₀₋₂N(R)C(═O)(CH₂)₀₋₂, (CH₂)₀₋₂C(═O)N(R)(CH₂)₀₋₂,(CH₂)₀₋₂N(R)C(═O)O(CH₂)₀₋₂, or (CH₂)₀₋₂OC(═O)N(R)(CH₂)₀₋₂;

L is a bond, NR, SO₂, C(═NR), C(═O)CR₂, C(═O)CH(N(R)C(═O)(C1-C4)alkyl,C(═O)CH(N(R)C(═O)O(C1-C4)alkyl, C(═O)CH(NR₂), C(═O)CR(halo), or is

wherein wavy lines indicate points of bonding,

or a pharmaceutically acceptable salt thereof.

For example, the compound can be of formula (IA)

wherein each of Ar¹, Ar², and Ar³ is independently selected aryl; X, L,R, and R′ are as defined herein.

For example, the compound can be of formula (IB)

wherein Ar¹ and Ar² are independently selected aryl and Ar³ isheteroaryl; X, L, R, and R′ are as defined herein.

For example, the compound can be of formula (IC)

whereinAr¹ is aryl, Ar² and Ar³ are independently selected heteroaryl; X, L, R,and R′ are as defined herein.

For example, the compound can be of formula (ID)

wherein Ar¹ and Ar³ are independently selected aryl, and Ar² isheteroaryl; X, L, R, and R′ are as defined herein.

For example, the compound can be of formula (IE)

wherein Ar¹ and Ar³ are independently selected heteroaryl, and Ar² isaryl; X, L, R, and R′ are as defined herein.

In various embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention and apharmaceutically acceptable excipient.

The invention further provides, in various embodiments, a method oftreatment of a cardiopulmonary disease in a patient afflicted therewith,comprising administering an effective amount of a compound of theinvention. For instance, the disease can be asthma or a chronicobstructive pulmonary disease; or, the disease can comprises sepsis; or,wherein the disease is coronary atherosclerosis. In various embodiments,the invention provides a method of treatment wherein the diseasecomprises a clinical syndrome characterized by bronchoconstriction,pulmonary fibrosis, coronary artery constriction, cytokine amplificationby dendritic cells, or the generation of disseminated intravascularcoagulopathy. More specifically, the invention provides a method oftreatment of a disease in a patient afflicted therewith wherein thedisease comprises inflammation by influenza infection, or wherein thedisease is cardiovascular disease, hypertension (including malignanthypertension), angina, myocardial infarction, cardiac arrhythmias,congestive heart failure, coronary heart disease, atherosclerosis,angina pectoris, dysrhythmias, cardiomyothopy (including hypertropiccardiomyothopy), heart failure, cardiac arrest, bronchitis, asthma,chronic obstructive pulmonary disease, cystic fibrosis, croup,emphysema, pleurisy, pulmonary fibrosis, pneumonia, pulmonary embolus,pulmonary hypertension, mesothelioma, ventricular conductionabnormalities, complete heart block, adult respiratory distresssyndrome, sepsis syndrome, idiopathic pulmonary fibrosis, scleroderma,systemic sclerosis, retroperitoneal fibrosis, prevention of keloidformation, or cirrhosis.

Accordingly, the invention provides, in various embodiments, a medicaluse comprising use of a compound of the invention, such as in apharmaceutical composition, for treatment of any of the above-enumeratedmedical conditions.

DETAILED DESCRIPTION Definitions

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise.

The term “about” as used herein, when referring to a numerical value orrange, allows for a degree of variability in the value or range, forexample, within 10%, or within 5% of a stated value or of a stated limitof a range.

The term “disease” or “disorder” or “malcondition” are usedinterchangeably, and are used to refer to diseases or conditions whereina sphingosine-1-phosphate receptor plays a role in the biochemicalmechanisms involved in the disease or malcondition or symptom(s) thereofsuch that a therapeutically beneficial effect can be achieved by actingon sphingosine-1-phosphate receptor, e.g. with an effective amount orconcentration of a synthetic ligand of the invention. “Acting on” asphingosine-1-phosphate receptor, or “modulating” asphingosine-1-phosphate receptor, can include binding to thesphingosine-1-phosphate receptor and/or inhibiting the bioactivity ofthe sphingosine-1-phosphate receptor and/or allosterically regulatingthe bioactivity of the sphingosine-1-phosphate receptor in vivo.

The expression “effective amount”, when used to describe therapy to anindividual suffering from a disorder, refers to the quantity orconcentration of a compound of the invention that is effective toinhibit or otherwise act on a sphingosine-1-phosphate receptor in theindividual's tissues wherein the sphingosine-1-phosphate receptorinvolved in the disorder, wherein such inhibition or other action occursto an extent sufficient to produce a beneficial therapeutic effect.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder or disease, orinhibition of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder, or curing thedisease or disorder. Similarly, as used herein, an “effective amount” ora “therapeutically effective amount” of a compound of the inventionrefers to an amount of the compound that alleviates, in whole or inpart, symptoms associated with the disorder or condition, or halts orslows further progression or worsening of those symptoms, or prevents,or provides prophylaxis for, the disorder or condition. In particular, a“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result. A therapeutically effective amount is also one inwhich any toxic or detrimental effects of compounds of the invention areoutweighed by, the therapeutically beneficial effects.

It is to be further understood that where descriptions of variousembodiments use the term “comprising,” those skilled in the art wouldunderstand that in some specific instances, an embodiment can bealternatively described using language “consisting essentially of” or“consisting of.”

By “chemically feasible” is meant a bonding arrangement or a compoundwhere the generally understood rules of organic structure are notviolated; for example a structure within a definition of a claim thatwould contain in certain situations, e.g., a pentavalent carbon atomthat would not exist in nature would be understood to not be within theclaim. The structures disclosed herein, in all of their embodiments areintended to include only “chemically feasible” structures, and anyrecited structures that are not chemically feasible, for example in astructure shown with variable atoms or groups, are not intended to bedisclosed or claimed herein.

When a substituent is specified to be an atom or atoms of specifiedidentity, “or a bond”, a configuration is referred to when thesubstituent is “a bond” that the groups that are immediately adjacent tothe specified substituent are directly connected to each other in achemically feasible bonding configuration.

All single enantiomer, diastereomeric, and racemic forms of a structureare intended, unless a particular stereochemistry or isomeric form isspecifically indicated. In several instances though an individualstereoisomer is described among specifically claimed compounds, thestereochemical designation does not imply that alternate isomeric formsare less preferred, undesired, or not claimed. Compounds used in thepresent invention can include enriched or resolved optical isomers atany or all asymmetric atoms as are apparent from the depictions, at anydegree of enrichment. Both racemic and diastereomeric mixtures, as wellas the individual optical isomers can be isolated or synthesized so asto be substantially free of their enantiomeric or diastereomericpartners, and these are all within the scope of the invention.

As used herein, the terms “stable compound” and “stable structure” aremeant to indicate a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into an efficacious therapeutic agent. Only stable compoundsare contemplated herein.

When a group is recited, wherein the group can be present in more than asingle orientation within a structure resulting in more than singlemolecular structure, e.g., a carboxamide group C(═O)NR, it is understoodthat the group can be present in any possible orientation, e.g.,X—C(═O)N(R)—Y or X—N(R)C(═O)—Y, unless the context clearly limits theorientation of the group within the molecular structure.

Substituted ring groups such as substituted cycloalkyl, aryl,heterocyclyl and heteroaryl groups also include rings and fused ringsystems in which a bond to a hydrogen atom is replaced with a bond to acarbon atom, or to a substituent group as defined above. Therefore,substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups canalso be substituted with alkyl, alkenyl, and alkynyl groups, or with thesubstituent groups listed above or other substituent groups know topersons of ordinary skill in the art.

By a “ring system” as the term is used herein is meant a moietycomprising one, two, three or more rings, which can be substituted withnon-ring groups or with other ring systems, or both, which can be fullysaturated, partially unsaturated, fully unsaturated, or aromatic, andwhen the ring system includes more than a single ring, the rings can befused, bridging, or spirocyclic.

Ring systems can be mono- or independently multi-substituted withsubstituents as are described above. By “spirocyclic” is meant the classof structures wherein two rings are fused at a single tetrahedral carbonatom, as is well known in the art.

As to any of the groups described herein, which contain one or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible. In addition, thecompounds of this disclosed subject matter include all stereochemicalisomers arising from the substitution of these compounds.

When a number of carbon atoms in a group, e.g., an alkyl, alkenyl,alkynyl, cycloalkyl, aryl, etc., is specified as a range, eachindividual integral number representing the number of carbon atoms isintended. For example, recitation of a (C₁-C₄)alkyl group indicates thatthe alkyl group can be any of methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, or tert-butyl. It is understood that aspecification of a number of carbon atoms must be an integer.

When a number of atoms in a ring is specified, e.g., a 3- to 9-memberedcycloalkyl or heterocyclyl ring, the cycloalkyl or heterocyclyl ring caninclude any of 3, 4, 5, 6, 7, 8, or 9 atoms. A cycloalkyl ring iscarbocyclic; a heterocyclyl ring can include atoms of any element inaddition to carbon capable of forming two or more bonds, e.g., nitrogen,oxygen, sulfur, and the like. The number of atoms in a ring isunderstood to necessarily be an integer.

Alkyl groups include straight chain and branched carbon-based groupshaving from 1 to about 20 carbon atoms, and typically from 1 to 12carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples ofstraight chain alkyl groups include those with from 1 to 8 carbon atomssuch as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl,and n-octyl groups. Examples of branched alkyl groups include, but arenot limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl,isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term“alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as wellas other branched chain forms of alkyl. Representative substituted alkylgroups can be substituted one or more times with any of the substituentgroups listed above, for example, amino, hydroxy, cyano, carboxy, nitro,thio, alkoxy, and halogen groups. Exemplary alkyl groups include, butare not limited to, straight or branched hydrocarbons of 1-6, 1-4, or1-3 carbon atoms, referred to herein as C₁₋₆alkyl, C₁₋₄alkyl, andC₁₋₃alkyl, respectively. Exemplary alkyl groups include, but are notlimited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl,3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, etc.

Cycloalkyl groups are groups containing one or more carbocyclic ringincluding, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, thecycloalkyl group can have 3 to about 8-12 ring members, whereas in otherembodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or7. Cycloalkyl groups further include polycyclic cycloalkyl groups suchas, but not limited to, norbornyl, adamantyl, bornyl, camphenyl,isocamphenyl, and carenyl groups, and fused rings such as, but notlimited to, decalinyl, and the like. Cycloalkyl groups also includerings that are substituted with straight or branched chain alkyl groupsas defined above.

Alkenyl groups include straight and branched chain and cyclic alkylgroups as defined above, except that at least one double bond existsbetween two carbon atoms. Thus, alkenyl groups have from 2 to about 20carbon atoms, and typically from 2 to 12 carbons or, in someembodiments, from 2 to 8 carbon atoms. Examples include, but are notlimited to vinyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂,—C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.Exemplary alkenyl groups include, but are not limited to, a straight orbranched group of 2-6 or 3-4 carbon atoms, referred to herein asC₂₋₆alkenyl, and C₃₋₄alkenyl, respectively. Exemplary alkenyl groupsinclude, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms in the ring. An aromatic compound, as is well-known in theart, is a multiply-unsaturated cyclic system that contains 4n+2 πelectrons where n is an integer. Thus aryl groups include, but are notlimited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl,fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl,chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In someembodiments, aryl groups contain about 6 to about 14 carbons in the ringportions of the groups. Aryl groups can be unsubstituted or substituted,as defined above. Representative substituted aryl groups can bemono-substituted or substituted more than once, such as, but not limitedto, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthylgroups, which can be substituted with carbon or non-carbon groups suchas those listed above.

Aralkyl, also termed arylalkyl, groups are alkyl groups as defined abovein which a hydrogen or carbon bond of an alkyl group is replaced with abond to an aryl group as defined above. Representative aralkyl groupsinclude benzyl and phenylethyl groups and fused (cycloalkylaryl)alkylgroups such as 4-ethyl-indanyl. Aralkenyl group are alkenyl groups asdefined above in which a hydrogen or carbon bond of an alkyl group isreplaced with a bond to an aryl group as defined above.

Heterocyclyl groups or the term “heterocyclyl” includes aromatic andnon-aromatic ring compounds containing 3 or more ring members, of whichone or more ring atom is a heteroatom such as, but not limited to, N, O,and S. Thus a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl,or if polycyclic, any combination thereof. In some embodiments,heterocyclyl groups include 3 to about 20 ring members, whereas othersuch groups have 3 to about 15 ring members. A heterocyclyl groupdesignated as a C₂-heterocyclyl can be a 5-ring with two carbon atomsand three heteroatoms, a 6-ring with two carbon atoms and fourheteroatoms and so forth. Likewise a C₄-heterocyclyl can be a 5-ringwith one heteroatom, a 6-ring with two heteroatoms, and so forth. Thenumber of carbon atoms plus the number of heteroatoms sums up to equalthe total number of ring atoms. Ring sizes can also be expressed by thetotal number of atoms in the ring, e.g., a 3- to 10-memberedheterocyclyl group, counting both carbon and non-carbon ring atoms. Aheterocyclyl ring can also include one or more double bonds. Aheteroaryl ring is an embodiment of a heterocyclyl group. The term“heterocyclyl group” includes fused ring species including thosecomprising fused aromatic and non-aromatic groups. For example, adioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenylring system) are both heterocyclyl groups within the meaning herein. Theterm also includes polycyclic, e.g., bicyclo- and tricyclo-ring systemscontaining one or more heteroatom such as, but not limited to,quinuclidyl.

Heterocyclyl groups can be unsubstituted, or can be substituted asdiscussed above. Heterocyclyl groups include, but are not limited to,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl,dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl,benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinylgroups. Representative substituted heterocyclyl groups can bemono-substituted or substituted more than once, such as, but not limitedto, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or6-substituted, or disubstituted with groups such as those listed above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12ring members. A heteroaryl group is a variety of a heterocyclyl groupthat possesses an aromatic electronic structure, which is amultiply-unsaturated cyclic system that contains 4n+2 it electronswherein n is an integer A heteroaryl group designated as a C₂-heteroarylcan be a 5-ring (i.e., a 5-membered ring) with two carbon atoms andthree heteroatoms, a 6-ring (i.e., a 6-membered ring) with two carbonatoms and four heteroatoms and so forth. Likewise a C₄-heteroaryl can bea 5-ring with one heteroatom, a 6-ring with two heteroatoms, and soforth. The number of carbon atoms plus the number of heteroatoms sums upto equal the total number of ring atoms. Heteroaryl groups include, butare not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl,azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinylgroups. Heteroaryl groups can be unsubstituted, or can be substitutedwith substituent groups as is discussed above. Representativesubstituted heteroaryl groups can be substituted one or more times withindependently selected groups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are notlimited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl,acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl),imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl),triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Any heterocyclyl or heteroaryl comprising nitrogen can be an N-oxide orN-metho salt or other N-quaternarized salt thereof; when a cationicN-quaternarized salt is present, it is understood that an anioniccounterion is present for charge balance. Any heterocyclyl or heteroarylcomprising sulfur can be an sulfoxide or sulfone or an S-metho salt orother S-alkylated salt thereof; when a cationic S-alkylated salt ispresent, it is understood that an anionic counterion is present forcharge balance.

The term “alkoxy” or “alkoxyl” refers to an oxygen atom connected to analkyl group, including a cycloalkyl group, as are defined above.Examples of linear alkoxy groups include but are not limited to methoxy,ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, and the like.Examples of branched alkoxy include but are not limited to isopropoxy,sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.Exemplary alkoxy groups include, but are not limited to, alkoxy groupsof 1-6 or 2-6 carbon atoms, referred to herein as C₁₋₆alkoxy, and C₂₋₆alkoxy, respectively. Exemplary alkoxy groups include, but are notlimited to methoxy, ethoxy, isopropoxy, etc.

An alkoxy group can include one to about 12-20 carbon atoms bonded tothe oxygen atom, and can further include double or triple bonds, and canalso include heteroatoms. For example, an allyloxy group is an alkoxygroup within the meaning herein. A methoxyethoxy group is also an alkoxygroup within the meaning herein, as is a methylenedioxy group in acontext where two adjacent atoms of a structures are substitutedtherewith.

The terms “halo” or “halogen” or “halide” by themselves or as part ofanother substituent mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine.

A “haloalkyl” group includes mono-halo alkyl groups, poly-halo alkylgroups wherein all halo atoms can be the same or different, and per-haloalkyl groups, wherein all hydrogen atoms are replaced by the same ordiffering halogen atoms, such as fluorine and/or chlorine atoms.Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl,1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, andthe like.

An “acyl” group as the term is used herein refers to a group containinga carbonyl moiety wherein the group is bonded via the carbonyl carbonatom. The carbonyl carbon atom is also bonded to another carbon atom,which can be part of an alkyl, aryl, aralkyl cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl group or the like. In the special case wherein thecarbonyl carbon atom is bonded to a hydrogen atom, the group is a“formyl” group, also an example of an acyl group as the term is definedherein. An acyl group can include 0 to about 12-20 additional carbonatoms bonded to the carbonyl group. An acyl group can include double ortriple bonds within the meaning herein. An acryloyl group is an exampleof a double bond-containing acyl group. An acyl group can also includeheteroatoms within the meaning here. A nicotinoyl group(pyridyl-3-carbonyl) group is an example of an acyl group within themeaning herein. Other examples include acetyl, benzoyl, phenylacetyl,pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When thegroup containing the carbon atom that is bonded to the carbonyl carbonatom contains a halogen, the group is termed a “haloacyl” group. Anexample is a trifluoroacetyl group.

The term “amine” includes primary, secondary, and tertiary amineshaving, e.g., the formula N(group)₃ wherein each group can independentlybe H or non-H, such as alkyl, aryl, and the like. Amines include but arenot limited to R—NH₂, wherein R is a carbon-based moiety, for example,alkylamines, arylamines, alkylarylamines; R₂NH wherein each R isindependently selected carbon-based moiety, such as dialkylamines,diarylamines, aralkylamines, heterocyclylamines and the like; and R₃Nwherein each R is independently selected carbon-based moiety, such astrialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, andthe like. The term “amine” as used herein also includes positivelycharged (cationic) forms such as amine salts and quaternarized amines.

An “amino” group is a substituent group of the form —NH₂, —NHR, —NR₂, or—NR₃ ⁺, wherein each R is an independently selected carbon-based group,and protonated forms of each, except for —NR₃ ⁺, which cannot beprotonated. Accordingly, any compound substituted with an amino groupcan be viewed as an amine. An “amino group” within the meaning hereincan be a primary, secondary, tertiary or quaternary amino group. An“alkylamino” group includes a monoalkylamino, dialkylamino, andtrialkylamino (trialkylammonium) group.

An “ammonium” ion includes the unsubstituted ammonium ion NH₄ ⁺, butunless otherwise specified, it also includes any protonated orquaternarized forms of amines. Thus, trimethylammonium hydrochloride andtetramethylammonium chloride are both ammonium ions, and amines, withinthe meaning herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR₂, and —NRC(O)R groups, respectively. Amide groups thereforeinclude but are not limited to primary carboxamide groups (—C(O)NH₂) andformamide groups (—NHC(O)H). A “carboxamido” group is a group of theformula C(O)NR₂, wherein R can be H, alkyl, aryl, etc.

Standard abbreviations for chemical groups such as are well known in theart are used; e.g., Me=methyl, Et=ethyl, i-Pr=isopropyl, Bu=butyl,t-Bu=tert-butyl, Ph=phenyl, Bn=benzyl, Ac=acetyl, Bz=benzoyl, and thelike.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄ ⁺ or thecations of various amines, including tetraalkyl ammonium salts such astetramethylammonium, or other cations such as trimethylsulfonium, andthe like. A “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt is a salt formed from an ion that has been approved forhuman consumption and is generally non-toxic, such as a chloride salt ora sodium salt. A “zwitterion” is an internal salt such as can be formedin a molecule that has at least two ionizable groups, one forming ananion and the other a cation, which serve to balance each other. Forexample, amino acids such as glycine can exist in a zwitterionic form. A“zwitterion” is a salt within the meaning herein. The compounds of thepresent invention may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases which are compounds of theinvention. Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility inprocess of synthesis, purification or formulation of compounds of theinvention.

“Pharmaceutically or pharmacologically acceptable” include molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. For human administration, preparations should meetsterility, pyrogenicity, and general safety and purity standards asrequired by FDA Office of Biologics standards.

Suitable pharmaceutically-acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid. Examples ofpharmaceutically unacceptable acid addition salts include, for example,perchlorates and tetrafluoroborates.

If a value of a variable that is necessarily an integer, e.g., thenumber of carbon atoms in an alkyl group or the number of substituentson a ring, is described as a range, e.g., 0-4, what is meant is that thevalue can be any integer between 0 and 4 inclusive, i.e., 0, 1, 2, 3, or4.

In various embodiments, the compound or set of compounds, such as areused in the inventive methods, can be any one of any of the combinationsand/or sub-combinations of the above-listed embodiments.

In various embodiments, a compound as shown in any of the Examples, oramong the exemplary compounds, is provided. Provisos may apply to any ofthe disclosed categories or embodiments wherein any one or more of theother above disclosed embodiments or species may be excluded from suchcategories or embodiments.

The compounds described herein can be prepared in a number of ways basedon the teachings contained herein and synthetic procedures known in theart. In the description of the synthetic methods described below, it isto be understood that all proposed reaction conditions, including choiceof solvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, can be chosen to be the conditionsstandard for that reaction, unless otherwise indicated. It is understoodby one skilled in the art of organic synthesis that the functionalitypresent on various portions of the molecule should be compatible withthe reagents and reactions proposed. Substituents not compatible withthe reaction conditions will be apparent to one skilled in the art, andalternate methods are therefore indicated. The starting materials forthe examples are either commercially available or are readily preparedby standard methods from known materials. All commercially availablechemicals were obtained from Aldrich, Alfa Aesare, Wako, Acros, Fisher,Fluka, Maybridge or the like and were used without further purification,except where noted. Dry solvents are obtained, for example, by passingthese through activated alumina columns.

The present invention further embraces isolated compounds of theinvention. The expression “isolated compound” refers to a preparation ofa compound of the invention, or a mixture of compounds the invention,wherein the isolated compound has been separated from the reagents used,and/or byproducts formed, in the synthesis of the compound or compounds.“Isolated” does not mean that the preparation is technically pure(homogeneous), but it is sufficiently pure to compound in a form inwhich it can be used therapeutically. Preferably an “isolated compound”refers to a preparation of a compound of the invention or a mixture ofcompounds of the invention, which contains the named compound or mixtureof compounds of the invention in an amount of at least 10 percent byweight of the total weight. Preferably the preparation contains thenamed compound or mixture of compounds in an amount of at least 50percent by weight of the total weight; more preferably at least 80percent by weight of the total weight; and most preferably at least 90percent, at least 95 percent or at least 98 percent by weight of thetotal weight of the preparation.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures and purified by standard techniques such asfiltration, liquid-liquid extraction, solid phase extraction,distillation, recrystallization or chromatography, including flashcolumn chromatography, or HPLC.

Tautomerism

Within the present invention it is to be understood that a compound ofthe formula (I) or a salt thereof may exhibit the phenomenon oftautomerism whereby two chemical compounds that are capable of facileinterconversion by exchanging a hydrogen atom between two atoms, toeither of which it forms a covalent bond. Since the tautomeric compoundsexist in mobile equilibrium with each other they may be regarded asdifferent isomeric forms of the same compound. It is to be understoodthat the formulae drawings within this specification can represent onlyone of the possible tautomeric forms. However, it is also to beunderstood that the invention encompasses any tautomeric form, and isnot to be limited merely to any one tautomeric form utilized within theformulae drawings. The formulae drawings within this specification canrepresent only one of the possible tautomeric forms and it is to beunderstood that the specification encompasses all possible tautomericforms of the compounds drawn not just those forms which it has beenconvenient to show graphically herein. For example, tautomerism may beexhibited by a pyrazolyl group bonded as indicated by the wavy line.While both substituents would be termed a 4-pyrazolyl group, it isevident that a different nitrogen atom bears the hydrogen atom in eachstructure.

Such tautomerism can also occur with substituted pyrazoles such as3-methyl, 5-methyl, or 3,5-dimethylpyrazoles, and the like. Anotherexample of tautomerism is amido-imido (lactam-lactim when cyclic)tautomerism, such as is seen in heterocyclic compounds bearing a ringoxygen atom adjacent to a ring nitrogen atom. For example, theequilibrium:

is an example of tautomerism. Accordingly, a structure depicted hereinas one tautomer is intended to also include the other tautomer.Optical Isomerism

It will be understood that when compounds of the present inventioncontain one or more chiral centers, the compounds may exist in, and maybe isolated as single and substantially pure enantiomeric ordiastereomeric forms or as racemic mixtures. The present inventiontherefore includes any possible enantiomers, diastereomers, racemates ormixtures thereof of the compounds of the invention.

The compounds of the invention, or compounds used in practicing methodsof the invention, may contain one or more chiral centers and, therefore,exist as stereoisomers. The term “stereoisomers” when used hereinconsist of all enantiomers or diastereomers. These compounds may bedesignated by the symbols “(+),” “(−),” “R” or “S,” depending on theconfiguration of substituents around the stereogenic carbon atom, butthe skilled artisan will recognize that a structure may denote a chiralcenter implicitly. The present invention encompasses variousstereoisomers of these compounds and mixtures thereof. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

The compounds of the disclosure may contain one or more double bondsand, therefore, exist as geometric isomers resulting from thearrangement of substituents around a carbon-carbon double bond. Thesymbol

denotes a bond that may be a single, double or triple bond as describedherein. Substituents around a carbon-carbon double bond are designatedas being in the “Z” or “E” configuration wherein the terms “Z” and “E”are used in accordance with IUPAC standards. Unless otherwise specified,structures depicting double bonds encompass both the “E” and “Z”isomers. Substituents around a carbon-carbon double bond alternativelycan be referred to as “cis” or “trans,” where “cis” representssubstituents on the same side of the double bond and “trans” representssubstituents on opposite sides of the double bond.

Compounds of the invention, or compounds used in practicing methods ofthe invention, may contain a carbocyclic or heterocyclic ring andtherefore, exist as geometric isomers resulting from the arrangement ofsubstituents around the ring. The arrangement of substituents around acarbocyclic or heterocyclic ring are designated as being in the “Z” or“E” configuration wherein the terms “Z” and “E” are used in accordancewith IUPAC standards. Unless otherwise specified, structures depictingcarbocyclic or heterocyclic rings encompass both “Z” and “E” isomers.Substituents around a carbocyclic or heterocyclic rings may also bereferred to as “cis” or “trans”, where the term “cis” representssubstituents on the same side of the plane of the ring and the term“trans” represents substituents on opposite sides of the plane of thering. Mixtures of compounds wherein the substituents are disposed onboth the same and opposite sides of plane of the ring are designated“cis/trans.”

Individual enantiomers and diastereomers of contemplated compounds canbe prepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, (3) direct separation of the mixture of opticalenantiomers on chiral liquid chromatographic columns or (4) kineticresolution using stereoselective chemical or enzymatic reagents. Racemicmixtures can also be resolved into their component enantiomers by wellknown methods, such as chiral-phase liquid chromatography orcrystallizing the compound in a chiral solvent. Stereoselectivesyntheses, a chemical or enzymatic reaction in which a single reactantforms an unequal mixture of stereoisomers during the creation of a newstereocenter or during the transformation of a pre-existing one, arewell known in the art. Stereoselective syntheses encompass both enantio-and diastereoselective transformations, and may involve the use ofchiral auxiliaries. For examples, see Carreira and Kvaerno, Classics inStereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.The priority of substituents is ranked based on atomic weights, a higheratomic weight, as determined by the systematic procedure, having ahigher priority ranking. Once the priority ranking of the four groups isdetermined, the molecule is oriented so that the lowest ranking group ispointed away from the viewer. Then, if the descending rank order of theother groups proceeds clockwise, the molecule is designated as having an(R) absolute configuration, and if the descending rank of the othergroups proceeds counterclockwise, the molecule is designated as havingan (S) absolute configuration. In the example in the Scheme below, theCahn-Ingold-Prelog ranking is A>B>C>D. The lowest ranking atom, D isoriented away from the viewer. The solid wedge indicates that the atombonded thereby projects toward the viewer out of the plane of the paper,and a dashed wedge indicates that the atom bonded thereby projects awayfrom the viewer out of the plan of the paper, i.e., the plane “of thepaper” being defined by atoms A, C, and the chiral carbon atom for the(R) configuration shown below.

A carbon atom bearing the A-D atoms as shown above is known as a“chiral” carbon atom, and the position of such a carbon atom in amolecule is termed a “chiral center.” Compounds of the invention maycontain more than one chiral center, and the configuration at eachchiral center is described in the same fashion.

There are various conventions for depicting chiral structures usingsolid and dashed wedges. For example, for the (R) configuration shownabove, the following two depictions are equivalent:

The present invention is meant to encompass diastereomers as well astheir racemic and resolved, diastereomerically and enantiomerically pureforms and salts thereof. Diastereomeric pairs may be resolved by knownseparation techniques including normal and reverse phase chromatography,and crystallization.

“Isolated optical isomer” or “isolated enantiomer” means a compoundwhich has been substantially purified from the corresponding opticalisomer(s) of the same formula. Preferably, the isolated isomer is atleast about 80%, more preferably at least 90% enantiomerically pure,even more preferably at least 98% enantiomerically pure, most preferablyat least about 99% enantiomerically pure, by weight. By “enantiomericpurity” is meant the percent of the predominant enantiomer in anenantiomeric mixture of optical isomers of a compound. A pure singleenantiomer has an enantiomeric purity of 100%.

Isolated optical isomers may be purified from racemic mixtures bywell-known chiral separation techniques. According to one such method, aracemic mixture of a compound of the invention, or a chiral intermediatethereof, is separated into 99% wt. % pure optical isomers by HPLC usinga suitable chiral column, such as a member of the series of DAICEL®CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo,Japan). The column is operated according to the manufacturer'sinstructions.

Another well-known method of obtaining separate and substantially pureoptical isomers is classic resolution, whereby a chiral racemic compoundcontaining an ionized functional group, such as a protonated amine orcarboxylate group, forms diastereomeric salts with an oppositely ionizedchiral nonracemic additive. The resultant diastereomeric salt forms canthen be separated by standard physical means, such as differentialsolubility, and then the chiral nonracemic additive may be eitherremoved or exchanged with an alternate counter ion by standard chemicalmeans, or alternatively the diastereomeric salt form may retained as asalt to be used as a therapeutic agent or as a precursor to atherapeutic agent.

Another aspect of an embodiment of the invention provides compositionsof the compounds of the invention, alone or in combination with anothermedicament. As set forth herein, compounds of the invention includestereoisomers, tautomers, solvates, prodrugs, pharmaceuticallyacceptable salts and mixtures thereof. Compositions containing acompound of the invention can be prepared by conventional techniques,e.g. as described in Remington: The Science and Practice of Pharmacy,19th Ed., 1995, or later versions thereof, incorporated by referenceherein. The compositions can appear in conventional forms, for examplecapsules, tablets, aerosols, solutions, suspensions or topicalapplications.

The compounds of the invention can be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of a malcondition. Such mammals include alsoanimals, both domestic animals, e.g. household pets, farm animals, andnon-domestic animals such as wildlife.

The compounds of the invention are effective over a wide dosage range.For example, in the treatment of adult humans, dosages from about 0.05to about 5000 mg, preferably from about 1 to about 2000 mg, and morepreferably between about 2 and about 2000 mg per day can be used. Atypical dosage is about 10 mg to about 1000 mg per day. In choosing aregimen for patients it can frequently be necessary to begin with ahigher dosage and when the condition is under control to reduce thedosage. The exact dosage will depend upon the activity of the compound,mode of administration, on the therapy desired, form in whichadministered, the subject to be treated and the body weight of thesubject to be treated, and the preference and experience of thephysician or veterinarian in charge.

Generally, the compounds of the invention are dispensed in unit dosageform including from about 0.05 mg to about 1000 mg of active ingredienttogether with a pharmaceutically acceptable carrier per unit dosage.

Usually, dosage forms suitable for oral, nasal, pulmonal or transdermaladministration include from about 125 μg to about 1250 mg, preferablyfrom about 250 μg to about 500 mg, and more preferably from about 2.5 mgto about 250 mg, of the compounds admixed with a pharmaceuticallyacceptable carrier or diluent.

Dosage forms can be administered daily, or more than once a day, such astwice or thrice daily. Alternatively dosage forms can be administeredless frequently than daily, such as every other day, or weekly, if foundto be advisable by a prescribing physician.

Evaluations

It is within ordinary skill to evaluate any compound disclosed andclaimed herein for effectiveness in inhibition of asphingosine-1-phosphate receptor and in the various cellular assaysusing the procedures described above or found in the scientificliterature. Accordingly, the person of ordinary skill can prepare andevaluate any of the claimed compounds without undue experimentation.

Any compound found to be an effective inhibitor of thesphingosine-1-phosphate receptor can likewise be tested in animal modelsand in human clinical studies using the skill and experience of theinvestigator to guide the selection of dosages and treatment regimens.

In various embodiments, the compound is any of those shown in Tables 1,2, or 3, below. Such compounds can be prepared by synthetic methodsdisclosed herein in combination with the knowledge of a person ofordinary skill in the art of organic synthesis, including the use ofappropriately selected precursors, intermediates, reagents, and reactionmechanisms.

While the invention has been described and exemplified in sufficientdetail for those skilled in this art to make and use it, variousalternatives, modifications, and improvements will be apparent to thoseskilled in the art without departing from the spirit and scope of theclaims.

All patents and publications referred to herein are incorporated byreference herein to the same extent as if each individual publicationwas specifically and individually indicated to be incorporated byreference in its entirety.

The terms and expressions which have been employed are used as terms ofdescription and not of limitation, and there is no intention that in theuse of such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theinvention claimed. Thus, it should be understood that although thepresent invention has been specifically disclosed by preferredembodiments and optional features, modification and variation of theconcepts herein disclosed may be resorted to by those skilled in theart, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

Description

Although published tool compounds provide for a valuableproof-of-concept, sphingolipid analogs that are amino-phosphate esters,in general do not have the necessary kinetics and stability for optimalusefulness. Our recent publications have documented key aspectsseparating the S1PR₁ from S1PR₃ binding pockets, (7, 46). Although thesystemic “immunosuppressive” actions of S1PR₁ modulators would betheoretically useful to dampen inflammation in localized environments,eg inflammation of the CNS in EAE or lung inflammation by influenzainfection (25, 47), S1PR₁ agonists would likely pose risks in sepsisbecause of bradycardia (6, 7) and their potential to increase lungmicrovascular permeability (48) (49). Thus, dampening systemicinflammation in sepsis with selective S1PR₃ antagonist devoid of S1P₁affinity is desired.

Recently, (Jo et al, 2012 and references therein) we described a modelof S1PR₃ based upon our published X-ray structure of the very similarS1PR₁ subtype (2). Using a combination of site-directed mutagenesis,ligand competition binding, functional assays, and molecular modeling,we demonstrated that the endogenous pan-S1P receptor agonist, S1P bindsto the orthosteric site as expected (50), that the novel S1PR₃ selectiveagonist CYM-5541 binds to an allosteric site and is therefore anallosteric agonist and that the S1PR₃ selective antagonist, SPM-242competes for binding to both the orthosteric and allosteric sites and issaid to be “bitopic’. The S1PR₃ selectivity of SPM-242 and CYM-5541, wasconcluded to come from binding to the less conserved, (non-orthosteric)regions of the S1P receptor family. In our quest for a drug-like S1PR₃antagonist, we chose to use the allosteric agonist CYM-5541 as ourstarting point. We hypothesize that by attaching other “drug-friendly’functional groups (—OH, —NR2, etc) onto the relatively low molecularweight CYM-5541 scaffold, we should be able to pick up accessory bindinggroups on the receptor such as hydrogen bonding to the peptide backboneor nearby side-chains such as Asn-95, Ser-99, Gln-281, Glu-115 andArg-114, resulting is a new bitopic ligand with enhanced solubilitycharacteristics.

TABLE 1 Specific Compounds of the Invention Cpd. ID Structure CYM-52146not I

CYM-52147 not I

CYM-52148 not I

CYM-52149 not I

CYM52150 IA

CYM52151 not I

CYM52152 not I

CYM52153 not I

CYM 52154 not I

CYM 52155 not I

CYM 52156 not I

CYM 52157 not I

CYM 52158 not I

CYM 52159 not I

CYM 52160 not I

CYM 52161 not I

CYM 52162 not I

CYM 52163 not I

CYM 52164 not I

CYM 52165 not I

CYM 52166 not I

CYM 52167 IB

CYM 52184 not I

CYM 52197 not I

CYM 52198 not I

CYM 52199 not I

CYM 52200 not I

CYM 52201 not I

CYM 52202 not I

CYM 52203 not 1

CYM 52204 not I

CYM 52205 IB

CYM 52206 not I

CYM 52207 IB

CYM 52208 not I

CYM 52209 not I

CYM 52210 not I

CYM 52211 not I

CYM 52212 not I

CYM 52213 not I

CYM 52214 not I

CYM 52215 not I

CYM 52216 not I

CYM 52217 not I

CYM 52218 not I

CYM 52219 not I

CYM 52246 IB

CYM 52247 IB

CYM 52248 IB

CYM 52249 IB

CYM 52250 IB

CYM 52251 IB

CYM 52252 IA

CYM 52253 IA

CYM 52254 IA

CYM 52255 IB

CYM 52256 IB

CYM 52257 IB

CYM 52258 IB

CYM 52259 60 IA

CYM 52260 not I

CYM 52264 IB

CYM 52266 IB

CYM 52267 IB

CYM 52268 IB

CYM 52269 not I

CYM 52270 not I

CYM 52271 not I

CYM 52272 not I

CYM 52273 not I

CYM 52274 IB

CYM 52276 IB

CYM 52289 IB

CYM 52290 not I

CYM 52291 not I

CYM 52294 IB

CYM 52295 not I

CYM 52296 IB

CYM 52297 IB

CYM 52298 IB

CYM 52299 IB

CYM 52300 IB

CYM 52301 IB

CYM 52302 IB

CYM 52303 not I

CYM 52304 IB

CYM 52305 IB

CYM 52306 IB

CYM 52307 IC

CYM 52308 IB

CYM 52309 IC

CYM 52310 IB

CYM 52311 IB

CYM 52312 IB

CYM 52313 IB

CYM 52314 IB

CYM 52315 IC

CYM 52316 IC

CYM 52317 IC

CYM 52318 not I

CYM 52319 not I

CYM 52320 IB

CYM 52321 IB

CYM 52322 IC

CYM 52323 IB

CYM 52324 not I

CYM 52325 IB

CYM 52326 IB

CYM 52327 not I

CYM 52328 not I

CYM 52329 IB

CYM 52330 IB

CYM 52331 IB

CYM 52332 IB

CYM 52333 IB

CYM 52334 IB

CYM 52335 IB

CYM 52336 IB

CYM 52337 IC

CYM 52338 IC

CYM 52339 IC

CYM 52340 not I

CYM 52341 not I

CYM 52342 not I

CYM 52343 IB

CYM 52344 IB

CYM 52345 not I

CYM 52346 not I

CYM 52347 not I not I

CYM 52348 not I

CYM 52349 not I

CYM 52350 not I

CYM 52351 IC

CYM 52352 IC

CYM 52353 IB

CYM 52354 IC

CYM 52355 IB

CYM 52356 IB

CYM 52357 not I

CYM 52358 not I

CYM 52359 IB

CYM 52360 not I

CYM 52361 not I

CYM 52362 not I

CYM 52363 not I

CYM 52364 IB

CYM 52365 IB

CYM 52366 IC

CYM 52367 IC

CYM 52368 IC

CYM 52369 IC

CYM 52370 IC

CYM 52371 IC

CYM 52372 IB

CYM 52373 IC

CYM 52374 IC

CYM 52375 IB

CYM 52376 IB

CYM 52377 IB

CYM 52378 IB

CYM 52379 IB

CYM 52380 IB

CYM 52381 IB

CYM 52382 IB

CYM 52383 IB

CYM 52384 IC

CYM 52385 not I

CYM 52386 not I

CYM 52387 IB

CYM 52388 IB

CYM 52389 IB

CYM 52390 IB

CYM 52391 IB

CYM 52392 IB

CYM 52393 IC

CYM 52394 IB

CYM 52395 IB

CYM 52396 IB

CYM 52397 IB

CYM 52398 IB

CYM 52399 IB

CYM 52400 IB

CYM 52401 IB

CYM 52402 IB

CYM 52403 IB

CYM 52404 IB

CYM 52405 IB

CYM 52406 IB

CYM 52407 IB

CYM 52408 IB

CYM 52409 IB

CYM 52410 IB

CYM 52411 IB

CYM 52412 IB

CYM 52413 IB

CYM 52414 IB

CYM 52415 IC

CYM 52416 IC

CYM 52417 IB

CYM 52418 IB

CYM 52419 IB

CYM 52420 IB

CYM 52421 IB

CYM 52422 not I

CYM 52423 IE

CYM 52424 IE

CYM 52425 IE

CYM 52426 IB

CYM 52427 IB

CYM 52428 IB

CYM 52429 IB

CYM 52430 IB

CYM 52431 IB

CYM 52432 IB

CYM 52433 IB

CYM 52434 IB

CYM 52435 IB

CYM 52436 IB

CYM 52437 IB

CYM 52438 IB

CYM 52439 IB

CYM 52440 IB

CYM 52441 IC

CYM 52442 IB

CYM 52443 IB

CYM 52444 IB

CYM 52445 IB

CYM 52446 IC

CYM 52447 IB

CYM 52448 IB

CYM 52449 IB

CYM 52450 IB

CYM 52451 IB

CYM 52452 IB

CYM 52453 IB

CYM 52454 IB

CYM 52455 IB

CYM 52456 IB

CYM 52457 IB

CYM 52458 IB

CYM 52459 IB

CYM 52460 IB

CYM 52461 IC

CYM 52462 IC

CYM 52463 IB

CYM 52464 IB

CYM 52465 IB

CYM 52466 IC

CYM 52467 IC

CYM 52468 IC

CYM 52469 IB

CYM 52470 IB

CYM 52471 IB

CYM 52472 IB

CYM 52473 IB

CYM 52474 IB

CYM 52475 IB

CYM 52476 IA

CYM 52477 IB

CYM 52478 IB

CYM 52479 IB

CYM 52480 IB

CYM 52481 IB

CYM 52482 IB

CYM 52483 IB

CYM 52484 IB

CYM 52485 IC

CYM 52486 IB

CYM 52487 IB

CYM 52488 IB

CYM 52489 IC

CYM 52490 IB

CYM 52491 IB

CYM 52492 IB

CYM 52493 IB

CYM 52494 IB

CYM 52495 IB

CYM 52496 IB

CYM 52497 IB

CYM 52498 IB

CYM 52499 IB

CYM 52500 IB

CYM 52501 IB

CYM 52502 IB

CYM 52503 IB

CYM 52504 IB

CYM 52505 IB

CYM 52506 IB

CYM 52507 IB

CYM 52508 IB

CYM 52509 IB

CYM 52510 IB

CYM 52511 IC

CYM 52512 IB

CYM 52513 not I

CYM 52514 IB

CYM 52515 IB

CYM 52516 IB

CYM 52517 IC

CYM 52518 IC

CYM 52519 IB

CYM 52520 IB

CYM52521 IB

CYM52522 IB

CYM52523 IB

CYM52524 IB

CYM52525 IB

CYM52526 IB

CYM52527 IB

CYM52528 IB

CYM52529 IB

CYM52530 IB

CYM52531 IC

CYM52532 IB

CYM 52533 IB

CYM 52534 IB

CYM 52535 IB

CYM 52536 IC

CYM 52542 IB

CYM 52543 IB

CYM 52544 IB

CYM 52545 IB

CYM 52546 IB

CYM 52547 IB

CYM 52548 IB

CYM 52549 IB

CYM 52550 IB

CYM 52551 IB

CYM 52552 IB

CYM 52553 IB

CYM 52554 IC

CYM 52555 IB

CYM 52556 IB

CYM 52557 IB

CYM 52558 IB

CYM 52559 IB

CYM 52560 IB

CYM 52561 not I

CYM 52562 IB

CYM 52563 IB

CYM 52564 IB

CYM 52565 IB

CYM 52566 IB

CYM 52567 IB

CYM 52568 IC

CYM 52569 IB

CYM 52570 IB

CYM 52571 IB

CYM 52572 IB

CYM 52573 IB

CYM 52574 IB

CYM 52575 IB

CYM 52576 IB

CYM 52577 IB

CYM 52578 IB

CYM 52579 IB

CYM 52580 IB

CYM 52581 IB

CYM 52582 IB

CYM 52583 IB

CYM 52584 IB

CYM 52585 IB

CYM 52586 IB

CYM 52587 IB

CYM 52588 IB

CYM 52589 IB

CYM 52590 IB

CYM 52591 IB

CYM 52592 IB

CYM 52593 IB

CYM 52594 IB

CYM 52595 IB

CYM 52596 IB

CYM 52597 IB

CYM 52598 IB

CYM 52599 IB

CYM 52600 IB

CYM 52601 IB

CYM 52602 IB

CYM 52603 IB

CYM 52604 IB

CYM 52605 IB

CYM 52606 IB

CYM 52607 IB

CYM 52608 IB

CYM 52609 IB

CYM 52610 IB

CYM 52611 IA

CYM 52612 IB

CYM 52613 IC

CYM 52614 IB

CYM 52615 IC

CYM 52616 IB

CYM 52617 IB

CYM 52618 IB

CYM 52619 IB

CYM 52620 IB

CYM 52621 IB

CYM 52622 IB

CYM 52623 IB

CYM 52624 IB

CYM 52625 IA

CYM 52626 IA

CYM 52627 IB

CYM 52628 IB

CYM 52629 IB

CYM 52630 IB

CYM 52631 IB

CYM 52632 IB

CYM 52633 IB

CYM 52634 IB

CYM 52635 IC

CYM 52636 IB

CYM 52637 IB

CYM 52638 IE

CYM 52639 IE

CYM 52640 IB

CYM 52641 IA

CYM 52642 ID

CYM 52643 IB

CYM 52644 IC

CYM 52645 IC

CYM 52646 IC

CYM 52647 IC

CYM 52648 IB

CYM 52649 IB

CYM 52650 IB

CYM 52651 IB

CYM 52652 IB

CYM 52653 IB

CYM 52654 IE

CYM 52655 IE

CYM 52656 IB

CYM 52657 IB

CYM 52658 IB

CYM 52659 IB

CYM 52660 IE

CYM 52661 IE

CYM 52662 IE

CYM 52663 IB

CYM 52664 IB

CYM 52665 IB

CYM 52666 IB

CYM 52667 IB

CYM 52668 IA

CYM 52669 IA

CYM 52670 IB

CYM 52671 IB

CYM 52672 IB

CYM 52673 IB

CYM 52674 IB

CYM 52675 IB

CYM 52676 IB

CYM 52677 IB

CYM 52678 IB

CYM 52679 IB

CYM 52680 IA

CYM 52681 IA

CYM 52682 IA

CYM 52683 IB

CYM 52684 IB

CYM 52685 IB

CYM 52686 IB

CYM 52687 IA

CYM 52688 IA

CYM 52689 IB

CYM 52690 IB

CYM 52691 IB

CYM 52692 IB

CYM 52693 IB

CYM 52694 IB

CYM 52695 IB

CYM 52696 IB

CYM 52697 IB

CYM 52698 IB

CYM 52699 IB

CYM 52700 IB

CYM 52701 Isomer 2 IB

CYM 52702 IB

CY 52703 IB

CYM 52704 not I

CYM 52705 IB

CYM-52706 IB

CYM-52707 IB

CYM-52708 IB

CYM-52709 IB

CYM-52710 IB

CYM-52711 IB

CYM-52712 IA

CYM-52713 IC

CYM-52714 ID OR IB

CYM-52715 IB

CYM52716 IB

CYM52717 IB

CYM52718 IB

CYM52719 isomer 1 IB

CYM52720 isomer 2 IB

CYM 52721 IB

CYM 52722 IB

CYM 52723 IB

CYM 52724 IB

CYM 52725 IB

CYM 52726 IA

CYM 52727 IB

CYM 52728 IA

CYM 52729 IB

CYM 52730 IB

CYM 52731 IB

CYM 52732 IB

CYM 52733 IA

CYM 52734 IB

CYM 52735 IB

CYM 52736 IB

CYM 52737 IB

CYM 52738 not I

CYM 52739 IB

CYM 52740 IB

CYM 52741 IA

CYM 52742 IA

CYM 52743 IA

CYM 52744 IB

CYM 52745 IA

CYM 52746 IB

CYM 52747 IB

CYM 52748 IB

CYM52749 IC

CYM52750 IB

CYM52751 IA

CYM52752 IB

CYM52753 not I

CYM52754 IB

CYM52755 IC

CYM 52756 IA

CYM 52757 IA

CYM 52758 IC

CYM 52759 IC

CYM 52760 IC

CYM 52761 IC

CYM 52762 IC

CYM 52763 IB

CYM 52764 IC

CYM 52765 not I

CYM 52766 IC

CYM 52767 IC

CYM 52768 IC

CYM 52769 IC

CYM 52770 IC

CYM 52771 IC

CYM 52772 ID

CYM 52773 ID

CYM 52774 IC

CYM 52775 IB

CYM 52776 IC

CYM 52777 ID

CYM 52778 IC

CYM 52779 IC

CYM 52780 IB

CYM 52781 IB

CYM 52782 IC

CYM 52783 IC

CYM 52784 IC

CYM 52785 IC

CYM 52786 IC

CYM 52787 IC

CYM 52788 IC

CYM 52789 IC

Boc = t-butoxycarbonyl

DOCUMENTS CITED

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(2010) Sphingosine 1-phosphate levels in    plasma and HDL are altered in coronary artery disease. Basic Res    Cardiol 105(6):821-832.-   32. Graler M H (2010) Targeting sphingosine 1-phosphate (SIP) levels    and SIP receptor functions for therapeutic immune interventions.    Cell Physiol Biochem 26(1):79-86.-   33. Kulakowska A, et al. (2010) Intrathecal increase of sphingosine    1-phosphate at early stage multiple sclerosis. Neurosci Lett    477(3):149-152.-   34. Watson L, et al. (2012) Increased serum concentration of    sphingosine-1-phosphate in juvenile-onset systemic lupus    erythematosus. J Clin Immunol 32(5):1019-1025.-   35. Christoffersen C, et al. (2011) Endothelium-protective    sphingosine-1-phosphate provided by HDL-associated apolipoprotein M.    Proc Natl Acad Sci USA 108(23):9613-9618.-   36. Christoffersen C & Nielsen L B (2012) Apolipoprotein M—a new    biomarker in sepsis. Crit Care 16(3):126.-   37. Dolgin E (2012) Trial failure prompts soul-searching for    critical-care specialists. Nat Med 18(7):1000.-   38. Annane D (2011) Corticosteroids for severe sepsis: an    evidence-based guide for physicians. Ann Intensive Care 1(1):7.-   39. Annane D (2008) Adrenal insufficiency in sepsis. Curr Pharm Des    14(19):1882-1886.-   40. Pan S, et al. (2006) A monoselective sphingosine-1-phosphate    receptor-1 agonist prevents allograft rejection in a stringent rat    heart transplantation model. Chem Biol 13(11):1227-1234.-   41. Zhang Z Y, et al. (2009) AUY954, a selective S1P(1) modulator,    prevents experimental autoimmune neuritis. J Neuroimmunol    216(1-2):59-65.-   42. Bajwa A, et al. (2012) Dendritic cell sphingosine 1-phosphate    receptor-3 regulates Th1-Th2 polarity in kidney ischemia-reperfusion    injury. J Immunol 189(5):2584-2596.-   43. Rathinasamy A, Czeloth N, Pabst O, Forster R, & Bernhardt    G (2010) The origin and maturity of dendritic cells determine the    pattern of sphingosine 1-phosphate receptors expressed and required    for efficient migration. J Immunol 185(7):4072-4081.-   44. Kuehn B M (2013) Guideline promotes early, aggressive sepsis    treatment to boost survival. JAMA 309(10):969-970.-   45. Oliveira C F, et al. (2008) Time- and fluid-sensitive    resuscitation for hemodynamic support of children in septic shock:    barriers to the implementation of the American College of Critical    Care Medicine/Pediatric Advanced Life Support Guidelines in a    pediatric intensive care unit in a developing world. Pediatr Emerg    Care 24(12):810-815.-   46. Schurer S C, et al. (2008) Ligand-binding pocket shape    differences between sphingosine 1-phosphate (S1P) receptors S1P1 and    S1P3 determine efficiency of chemical probe identification by    ultrahigh-throughput screening. 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Examples

Compounds are presented that selectively modify the action(s) ofSphingosine-1-Phosphate Receptors (S1P-R's) and therefore have potentialfor the treatment(s) of diseases or disorders of the cardiovascularand/or pulmonary systems. These diseases/disorders include but are notlimited to:

Cardiovascular disease, hypertension (including malignant hypertension),angina, myocardial infarction, cardiac arrhythmias, congestive heartfailure, Coronary heart disease, atherosclerosis, angina pectoris,dysrhythmias, cardiomyothopy (including hypertropic cardiomyothopy),heart failure, cardiac arrest, bronchitis, asthma, chronic obstructivepulmonary disease, cystic fibrosis, croup, emphysema, pleurisy,pulmonary fibrosis, pneumonia, pulmonary embolus, pulmonaryhypertension, mesothelioma, Ventricular Conduction abnormalities,Complete Heart Block Adult Respiratory Distress Syndrome and SepsisSyndrome, Idiopathic Pulmonary fibrosis, scleroderma, systemicsclerosis, retroperitoneal fibrosis, prevention of keloid formation,cirrhosis.

Compounds of the invention below have been shown to demonstrate activityas antagonist/agonist of one or more of the knownsphingosine-1-phosphate receptors with IC₅₀/EC₅₀ values lower than 10micromolar. Representative examples are given in Tables 2 and 3, below.

TABLE 2 CYM S1P1 S1P2 Generic AA IC₅₀ AA IC₅₀ S1P3AA S1P4AA S1P5AAformula Structure μM μM IC₅₀ μM IC₅₀ μM IC₅₀ μM 52274 IB

— — 0.772 44.0 — 52276 IB

— — 17.2 >50 — 52296 IB

— 39.7 10.3 35.4 — 52297 IB

— >50 1.9 >50 — 52298 IB

— >50 >50 >50 — 52299 IB

— 29.7 2.2 39.1 — 52294 IB

— >50 1.6 5.7 — 52331 IB

— 14.7 0.667 21.3 — 52332 IB

— 15.9 1.5 17.9 — 52351 IB

— >50 4.2 >50 — 52355 IB

— >50 26 >50 — 52356 IB

— >50 9.8 >50 — 52394 IB

— 1.0 0.246 0.873 — 52396 IB

— 44.3 30.8 >50 — 52397 IB

— 30.8 8.8 21.6 — 52398 IB

— 21.7 3.1 12.7 — 52399 IB

— >50 8.4 28.2 — 52433 IB

— >50 0.649 15.1 — 52434 IB

— 29.4 0.317 9.9 — 52435 IB

— 32.2 1.6 8.2 — 52442 IB

— >50 0.07 9.3 — 52458 IB

— 38.3 0.943 9.8 — 52459 IB

— 24.6 0.236 8.2 — 52460 IB

— >50 0.09 8.8 — 52464 IB

— >50 0.022 8.3 — 52474 IB

0.227 >50 0.014 >50 — 52475 IB

37.2 37.3 0.082 >50 — 52476 IB

>28 >50 0.906 >50 — 52483 IB

0.91 >50 0.097 6.5 — 52484 IB

9.3 43.8 0.826 11.5 — 52486 IB

1.3 >50 0.028 >50 — 52487 IB

0.347 >50 0.113 17.5 — 52488 IB

0.197 >50 0.079 5.6 — 52489 IC

2.7 >50 0.567 26.6 — 52491 IB

>28 >50 3.9 30.6 — 52492 IB

>28 >50 5.1 >50 — 52495 IB

>28 15.6 9.8 >50 — 52504 IB

2.8 — 0.152 — — 52505 IB

>50 — 0.576 — — 52506 IB

1.5 — 0.172 — — 52507 IB

2.2 — 0.112 — — 52508 IB

>50 — 0.796 — — 52509 IB

>50 — 2.5 — — 52510 IB

0.899 — 0.213 — — 52511 IC

6.4 — 0.308 — — 52512 IB

25.5 — 4.1 — — 52514 IB

>50 — 29.6 — — 52520 IB

0.22 >50 0.035 16.2 — 52522 IB

3.6 — 0.39 — — 52523 IB

7.3 — 0.168 — — 52524 IB

>50 — 0.065 — — 52525 IB

2.0 — 0.076 — — 52526 IB

1.8 6.7 0.027 >50 — 52527 IB

0.204 — 0.032 — — 52528 IB

1.4 — 0.063 — — 52529 IB

1.4 44.9 0.041 18.8 — 52530 IB

0.333 — 0.040 — — 52531 IC

>50 — 2.7 — — 52543 IB

17.6 — 0.405 — — 52544 IB

>28 — 9.1 — — 52545 IB

3.5 — 0.792 — — 52547 IB

1.9 — 0.249 — — 52548 IB

3.2 — 0.13 — — 52551 IB

>28 — 0.964 — — 52552 IB

10.2 — 1.0 — — 52553 IB

0.574 — 0.147 — — 52555 IB

7.1 >50 0.057 8.5 — 52556 IB

0.285 — 0.061 — — 52558 IB

1.4 — 0.057 — — 52559 IB

0.604 44.7 0.016 14.8 — 52560 IB

2.3 19.9 0.038 22.1 — 52562 IB

5.3 >50 0.042 20.9 — 52563 IB

17.2 — 0.114 — — 52564 IB

>28 — 3.7 — — 52566 IB

>28 — 10.3 52568 IC

6.3 14.1 0.052 10.3 — 52571 IB

4.4 >50 0.29 25.4 — 52572 IB

0.81 18.9 0.013 34.4 — 52573 IB

1.1 40.0 0.032 28.8 — 52574 IB

2.1 — 0.092 — — 52575 IB

1.5 24.3 0.034 21.4 — 52576 IB

7.8 — 0.077 — — 52577 IB

>28 >50 0.026 >50 — 52578 IB

1.7 32.6 0.029 13.6 — 52579 IB

1.1 44.8 0.016 >50 — 52580 IB

0.141 >50 0.007 24.8 — 52581 IB

0.566 >50 0.009 14.1 — 52582 IB

0.308 >50 0.018 27.6 — 52583 IB

1.1 >50 0.032 23.1 — 52584 IB

0.505 >50 0.02 38.9 — 52585 IB

17.9 — 0.21 — — 52586 IB

10 — 0.154 — — 52587 IB

19 — 0.135 — — 52589 IB

31.8 — 1.1 — — 52590 IB

2.1 — 1.0 — — 52591 IB

1.4 — 1.5 — — 52592 IB

10.6 — 0.863 — — 52593 IB

9.3 — 1.8 — — 52594 IB

2.5 — 1.3 — — 52595 IB

2.7 44.8 0.012 16.5 — 52596 IB

0.878 12.5 0.012 >50 — 52597 IB

0.332 43.2 0.026 >50 — 52598 IB

5.1 — 0.350 — — 52599 IB

23.3 — 3.5 — — 52600 IB

6.4 — 0.396 — — 52601 IB

1.4 13.5 0.03 26.8 — 52602 IB

3.2 — 0.073 — — 52603 IB

0.389 — 0.048 — — 52604 IB

0.099 35.4 0.010 23.5 — 52605 IB

0.4 — 0.228 — — 52606 IB

>28 12.0 0.157 >50 — 52607 IB

0.452 12.0 0.021 >50 — 52608 IB

>28 — 0.253 — — 52609 IB

>28 19.6 0.042 16.1 — 52610 IB

5 — 0.647 — — 52612 IB

>28 — 0.456 — — 52613 IC

10.4 — 0.257 — — 52614 IB

>28 — 0.581 — — 52615 IC

1.4 — 0.098 — — 52616 IB

4.1 — 0.15 — — 52617 IB

4.1 17.3 0.031 11.7 — 52618 IB

>28 — 3.2 — — 52619 IB

7 — 0.551 — — 52620 IB

>28 — 1.7 — — 52621 IB

>28 — 19.2 — — 52622 IB

>28 — 7.6 — — 52624 IB

>28 — 9.2 — — 52625 IA

>28 — 0.248 — — 52626 IA

>28 — 0.113 — — 52627 IB

>28 >50 0.104 >50 — 52628 IB

4 — 0.036 — — 52629 IB

1.1 — 0.042 — — 52630 IB

>28 — 0.416 — — 52631 IB

1.6 — 0.042 — — 52632 IB

0.177 — 0.02 — — 52633 IB

1.6 — 0.026 — — 52634 IB

0.133 — 0.018 — — 52635 IC

8.1 — 0.122 — — 52637 IB

>28 — 32.3 — — 52638 IB

>28 — 0.645 — — 52639 IB

>28 — 0.4 — — 52640 IB

>28 — 1.7 — — 52641 IA

>28 — 0.113 — — 52642 ID

11.1 — 1.7 — — 52646 IC

2.5 — 0.329 — — 52647 IC

9.5 — 0.629 — — 52649 IB

>28 — 0.95 — — 52650 IB

>28 — 0.834 — — 52651 IB

>28 — 0.096 — — 52652 IB

3.7 — 0.137 — — 52653 IB

>28 — 1.6 — — 52654 IB

>28 — 2 — — 52655 IB

>28 — 2.3 — — 52656 IB

4.0 — 1.2 — — 52657 IB

4.5 — 0.439 — — 52660 IE

>28 — 0.442 — — 52661 IE

>28 — 0.345 — — 52662 IC

>28 — 1.1 — — 52664 IB

1.4 — 0.013 — — 52665 IB

>28 — 0.121 — — 52666 IB

0.528 — 0.028 — — 52667 IB

6.6 — 16.3 — — 52668 IA

>28 — 0.679 — — 52669 IA

27.5 — 2.8 — — 52670 IB

0.452 — 0.011 — — 52671 IB

1.8 — 0.011 — — 52672 IB

1.4 — 0.051 — — 52673 IB

3.3 — 0.076 — — 52674 IB

6.4 — 0.027 — — 52675 IB

>28 — 0.214 — — 62676 IB

12.0 — 0.301 — — 52677 IB

0.621 — 0.033 — — 52678 IB

1.5 — 0.023 — — 52679 IB

>28 — 3.1 — — 52680 IA

>28 — 0.037 — — 52682 IA

>28 — 0.672 — — 52683 IB

18.4 — 0.124 — — 52684 IB

>28 — 0.075 — — 52685 IB

3.3 — 0.056 — — 52686 IB

6.6 — 0.047 — — 52687 IA

22.4 — 0.426 — — 52688 IA

>28 — 3.3 — — 52689 IB

10.2 — 0.392 — — 52690 IB

>28 — 0.492 — — 52691 IB

>28 — 6.8 — — 52692 IB

>28 — 7.3 — — 52693 IB

>28 — 2.1 — — 52694 IB

>28 — 1.4 — — 52695 IB

>28 — 2.1 — — 52696 IB

>28 — 2.2 — — 52697 IB

>28 — 0.049 — — 52698 IB

4 — 0.063 — — 52699 IB

>28 — 0.447 — — 52700 IB

>28 — 0.627 — — 52702 IB

>28 — 0.542 — — 52703 IB

>28 — 0.641 — — 52705 IB

4.7 — 0.048 — — 52706 IB

4.5 — 0.153 — — 52707 IB

26.2 — 0.511 — — 52708 IB

>28 — 0.527 — — 52709 IB

3.7 — 0.035 — — 52710 IB

16.1 — 5.3 — — 52711 IB

5.3 — 0.04 — — 52713 IC

0.923 — 0.014 — — 52715 IB

>28 — 1.6 — — 52716 IB

0.21 — 0.018 — — 52717 IB

12.7 — 0.096 — — 52718 IB

0.86 — 0.006 — — 5271IB

  isomer 1 >28 — 11.9 — — 52720 IB

  isomer 2 5.1 — 0.211 — — 52721 IB

10 — 0.068 — — 52722 IB

2.6 — 0.057 — — 52723 IB

3.1 — 0.021 — — 52724 IB

1.3 — 0.033 — — 52725 IB

>28 — 1.0 — — 52726 IA

22.3 — 2.0 — — 52727 IB

3.6 — 0.057 — — 52728 IA

>28 — 0.304 — — 52729 IB

27.4 — 0.151 — — 52730 IB

9.5 — 0.039 — — 52731 IB

22.1 — 0.231 — — 52732 IB

0.886 — 1.1 — — 52733 IA

>28 — 3.1 — — 52734 IB

>28 — 1.5 — — 52735 IB

>28 — 20.4 — — 52736 IB

14.2 — 3.5 — — 52737 IB

13.5 — 12.1 — — 52739 IB

18.5 — 0.079 — — 52740 IB

10.1 — 0.927 — — 52741 IA

>28 — 0.396 — — 52742 IA

>28 — 0.342 — — 52743 IA

>28 — 0.33 — — 52744 IB

>28 — 0.349 — — 52745 IA

>28 — 2.2 — — 52749

0.199 — 0.019 — — 52750

4.3 — 0.046 — — 52751

>28 — 4.4 — — 52752

7.8 — 0.164 — — 52754

6.0 — 0.189 — — 52755

3.9 — 2.7 — — 52756

>28 — 0.489 — — 52759

0.352 — 0.027 — — 52760

>28 — 0.439 — — 52761

1.5 — 0.133 — — 52763

3.0 — 0.682 — — 52764

4.3 — 0.251 — — 52766

1.6 — 0.112 — — 52767

15.4 — 0.445 — — 52768

1.2 — 0.088 — — 52770

0.636 — 0.040 — — 52771

0.268 — 0.036 — — 52772

>28 — 1.2 — — 52773

>28 — 0.485 — — 52774

>28 — 1.1 — — 52776

0.858 — 3.5 — — 52777

3.2 — 3.2 — — 52780

5.6 — 0.091 — — 52781

0.939 — 0.105 — — 52782

1.5 — 0.105 — — 52783

0.537 — 0.048 — — 52784

0.088 — 0.030 — — 52785

9.2 — 2.4 — — 52786

5.8 — 0.540 — — 52787

14.3 — 0.438 — — 52789

3.8 — 0.451 — —

TABLE 3 S1P1 S1P2 CYM AA AA Generic IC₅₀ IC₅₀ S1P3AA S1P4AA S1P5AAformula Structure μM μM IC₅₀ μM IC₅₀ μM IC₅₀ μM 52167 IB

— — 0.7 5.2 — 52205 IB

— — 4.3 34 — 52207 IB

— — 1.3 30.4 — 52304 IB

7.9 >50 1.2 7.8 21.8 52305 IB

1.6 >50 0.521 >50 >50 52306 IB

0.881 2.8 0.586 2.6 5.1 52307 IC

— >50 0.899 >50 — 52308 IB

>50 >50 3.9 >50 >50 52310 IB

— >50 3.5 >50 — 52311 IB

— >50 2.3 30.2 — 52312 IB

— >50 3.1 >50 — 52313 IB

— >50 2.2 >50 — 52321 IB

— >50 2.4 39.7 >50 52325 IB

— >50 2.8 >50 — 52326 IB

— >50 3.4 >50 — 52333 IB

— >50 3.8 >50 — 52335 IB

1.6 >50 0.415 >50 >50 52336 IB

— >50 1.7 >50 — 52337 IC

7.3 >50 2.8 >50 25.1 52339 IC

— 23.4 1.2 5.9 — 52341 IB

1.8 >50 3.3 >50 >50 52346 IB

— 5.2 5.7 5.1 — 52357 IB

2.1 >50 2.8 12.9 >50 52364 IB

17.5 >50 0.368 >50 >50 52365 IB

>50 >50 0.214 14.3 >50 52379 IB

>50 >50 2.9 >50 >50 52386 IB

>50 43.7 5.7 21.6 12.4 52387 IB

0.392 >50 0.229 >50 >50 52388 IB

0.456 >50 0.104 5.2 5.1 52389 IB

— >50 5.3 >50 — 52390 IB

>50 >50 1.1 >50 >50 52391 IB

9.5 >50 0.278 30.5 16.1 52392 IB

0.564 >50 0.108 >50 >50 52393 IC

— >50 6.4 >50 — 52401 IB

— >50 0.226 21.2 — 52402 IB

>50 >50 0.214 >50 >50 52403 IB

10.1 >50 0.39 >50 >50 52404 IB

— >50 0.376 37.9 — 52405 IB

— >50 2.0 >50 — 542406 IB

>50 >50 0.406 >50 >50 52407 IB

4.0 >50 0.219 >50 39.4 52408 IB

— >50 0.898 >50 — 52409 IB

— >50 0.381 >50 — 52412 IB

— >50 3.7 24.2 — 52415 IC

— >50 0.556 25.4 — 52416 IC

— >50 0.411 22.2 — 52419 IB

0.823 >50 0.053 34.6 20 52420 IB

0.426 >50 0.066 >50 >50 52421 IB

2.7 >50 0.211 >50 >50 52426 IB

— >50 2.15 >50 — 52427 IB

— >50 0.111 17.5 — 52428 IB

— >50 0.198 23.3 — 52429 IB

1.2 >50 0.076 38.5 16.2 52430 IB

0.112 >50 0.033 >50 >50 52436 IB

— >50 0.264 >50 — 52438 IB

9.6 >50 0.32 3.1 17.1 52439 IB

— >50 0.584 44.8 — 52440 IB

— >20 0.086 >50 — 52441 IB

— >30 2.5 20.3 — 52445 IB

— >50 1.5 17.1 — 52446 IC

— 22.7 0.370 9.2 — 52447 IB

— >50 0.26 >50 — 52449 IB

— >50 0.219 16.3 — 52450 IB

— >50 0.184 19.2 — 52451 IB

— 8.7 0.475 >50 — 52453 IB

— 10.9 0.215 6.7 — 52454 IB

— >50 0.24 >50 — 52455 IB

— >50 0.091 12.4 — 52456 IB

— >50 0.201 38.4 — 52457 IB

— >50 0.06 >50 — 52461 IC

— >50 0.045 19.9 — 52462 IC

— 35 6.6 42.3 29.5 52463 IB

— 43.1 0.341 15.5 — 52465 IB

— 44.5 0.175 8.6 — 52466 IC

— >50 1.1 28.7 — 52469 IB

6.2 10.5 1.4 15.7 — 52470 IB

20.1 >50 0.382 >50 — 52471 IB

0.475 31.1 0.214 >50 — 52472 IB

>28 >50 0.113 >50 — 52473 IB

>28 >50 1.7 >50 — 52477 IB

>28 >50 3.2 >50 — 52478 IB

17.9 >50 1.1 >50 — 52479 IB

1.2 >50 0.31 >50 — 52480 IB

0.39 >50 0.147 >50 — 52481 IB

1.5 >50 0.425 >50 — 52482 IB

3.5 >50 0.319 >50 — 52485 IC

3.5 >50 0.984 >50 — 52498 IB

34.3 — 0.166 — — 52499 IB

40.5 — 0.429 — — 52500 IB

0.959 — 0.095 — — 52501 IB

22.2 — 0.839 — — 52502 IB

1.4 — 0.109 — — 52503 IB

0.527 — 0.147 — — 52515 IB

>50 — 0.685 — — 52518 IC

9.8 — 1.5 — — 52519 IB

>50 — 0.194 — — 52532 IB

2.0 — 0.405 — — 52534 IB

8.4 — 2.2 — — 52536 IC

>50 — 4.9 — — 52569 IB

>28 — 2.2 — — 52636 IB

1.9 — 0.098 — — 52648 IB

0.401 — 0.046 — — 52588 IB

0.392 — 0.047 — — Boc = t-butoxycarbonyl Ph = phenyl Rac = racemate; allcompounds as shown include all stereoisomers unless otherwise indicated.Isomer 1, isomer 2; indicates separated stereoisomers of a structure,but absolute configuration unstated.General Synthetic Schemes:

A mixture of I, II and Ti(OEt)₄ in a sealed tube was heated at 70° C.for 30 min. The mixture was dissolved in EtOAc and washed with brine.The organic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The product III was used without further purification.To a solution of III in THF at −78° C. was slowly added aryl magnesiumbromide IV and the reaction was stirred for 2 h. The mixture wasquenched with a saturated solution of ammonium chloride and the productextracted with EtOAc. The organic phase was dried over anhydrous Na₂SO₄and concentrated in vacuo, followed by the purification of product V bycolumn chromatography (CC) using hexanes/EtOAc. To a solution of V inMeOH was added a 4M solution of HCl in dioxane and the reaction wasstirred for 30 min at room temperature (rt). The mixture wasconcentrated under reduced pressure and the product VI used withoutfurther purification. A solution of VI, the appropriated carboxylicacid, EDCI, HOBt and DIPEA in dichloromethane was stirred at rt for 2 h.The mixture was concentrated under reduced pressure and the product VIIpurified by HPLC.

A mixture of the appropriate aryl chloride (VIII or X), VI and DIPEA inEtOH was heated with microwave irradiation at 130° C. for 30 minutes toafford the corresponding products (IX or XI) that were purified by HPLC.

A mixture of XII, XIII and catalytic amount of formic acid in EtOH washeated at 60° C. overnight. The crude was concentrated and purified byCC using hexanes/EtOAc. To a solution of XIV in THF at 0° C. was addeddropwise a solution of XV in Et₂O; the reaction mixture was stirredovernight at it. The mixture was quenched with a saturated solution ofammonium chloride and the product extracted with EtOAc. The organicphase was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The product XVI was purified by CC using hexanes/EtOAc orHPLC.

In a microwave vial a stirring solution of XVII in dioxane was treatedwith HOBt and EDCI at rt. The reaction was stirred for 10 minutesfollowed by the addition of XVIII. The reaction was stirred foradditional 30 minutes at rt, then heated to 110° C. under microwaveirradiation for 30 minutes. To the reaction was added brine and theproduct was extracted with EtOAc (3×). The organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The productXIX was purified by CC using hexanes/EtOAc. A solution of XIX indichloromethane was stirred with TFA at rt for 20 minutes. The mixturewas concentrated under reduced pressure and the product used withoutfurther purification. A solution of the TFA salt, the appropriatecarboxylic acid, EDCI, HOBt and DIPEA in dichloromethane was stirred atrt for 2 h. The mixture was concentrated under reduced pressure and theproduct XX purified by HPLC.

What is claimed is:
 1. A compound of formula (TB)

wherein Ar¹ and Ar² are each independently selected (C6-C10)aryl and Ar³is a (5- to 10-membered)heteroaryl; wherein any aryl or heteroaryl ringsystem of AO, Ar², or Ar³ is optionally fused with a cycloalkyl or aheterocyclyl ring; wherein any aryl or heteroaryl of Ar¹, Ar², or Ar³ iseach optionally independently mono- or multi-substituted with up tothree substituents selected from the group consisting of (C1-C4)alkyl,(C2-C4)alkenyl, halo, halo(C1-C4)alkyl, monohydroxy(C1-C4)alkyl,dihydroxy(C2-C4)alkyl, monohydroxy(C1-C4)alkoxy, dihydroxy(C2-C4)alkoxy,(C2-C6)acyl, (C1-C6)alkoxycarbonyl(CH₂)₀₋₂, carboxy(CH₂)₀₋₂, oxo, cyano,NR₂(CH₂)₀₋₂, NR₂C(═O)(CH₂)₀₋₂, NR₂C(═O)(CH₂)₀₋₂O(CH₂)₀₋₂,(C1-C4)C(═O)N(R), (C1-C4)OC(═O)N(R), C═NOR, (C3-C10)cycloalkyl, (5- to10-membered)heterocyclyl, (C6-C10)aryl, and (5- to 10-membered)heteroaryl; wherein any cycloalkyl, heterocyclyl, aryl or heteroarylsubstituent of AO, Ar², or Ar³ is itself optionally substituted with upto three secondary substituents selected from the group consisting of(C1-C4)alkyl, (C2-C4)alkenyl, halo, halo(C1-C4)alkyl, OH,monohydroxy(C1-C4)alkyl, dihydroxy(C2-C4)alkyl,monohydroxy(C1-C4)alkoxy, dihydroxy(C2-C4)alkoxy, (C1-C4)alkoxy,(C2-C6)acyl, (C1-C6)alkoxycarbonyl(CH₂)₀₋₂, carboxy(CH₂)₀₋₂, oxo, cyano,NR₂(CH₂)₀₋₂, NR₂C(═O)(CH₂)₀₋₂, NR₂C(═O)(CH₂)₀₋₂O(CH₂)₀₋₂,(C1-C4)C(═O)N(R), (C1-C4)OC(═O)N(R), and C═NOR; each R is independentlyH, (C1-C4)alkyl, hydroxy(C2-C4)alkyl, cyano, or((C1-C4)alkyl-O)₁₋₂(C1-C4)alkyl, or two R groups together with an atomto which they are both joined can form a ring; each R′ is independentlyH, (C1-C4)alkyl, hydroxy(C2-C4)alkyl, (CH₂)₀₋₂C(═O)O(C1-C4)alkyl, or(C3-C6)cycloalkyl;

wherein X is NR and L is a bond or is C(═O), or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein Ar³ ispyridyl or quinolyl.
 3. The compound of claim 1, wherein Ar¹ and Ar² arephenyl.
 4. A pharmaceutical composition comprising a compound of claim 1and a pharmaceutically acceptable excipient.
 5. A method of treatment ofa cardiopulmonary disease in a patient afflicted therewith, comprisingadministering an effective amount of a compound of claim
 1. 6. Themethod of claim 5, wherein the disease is asthma or a chronicobstructive pulmonary disease.
 7. The method of claim 5, wherein thedisease comprises sepsis.
 8. The method of claim 5, wherein the diseaseis coronary atherosclerosis.
 9. The method of claim 5, wherein thedisease comprises a clinical syndrome characterized bybronchoconstriction, pulmonary fibrosis, coronary artery constriction,cytokine amplification by dendritic cells, or the generation ofdisseminated intravascular coagulopathy.
 10. The method of claim 5,wherein the disease comprises inflammation by influenza infection. 11.The method of claim 5, wherein the disease is cardiovascular disease,hypertension (including malignant hypertension), angina, myocardialinfarction, cardiac arrhythmias, congestive heart failure, coronaryheart disease, atherosclerosis, angina pectoris, dysrhythmias,cardiomyothopy (including hypertropic cardiomyothopy), heart failure,cardiac arrest, bronchitis, asthma, chronic obstructive pulmonarydisease, cystic fibrosis, croup, emphysema, pleurisy, pulmonaryfibrosis, pneumonia, pulmonary embolus, pulmonary hypertension,mesothelioma, ventricular conduction abnormalities, complete heartblock, adult respiratory distress syndrome, sepsis syndrome, idiopathicpulmonary fibrosis, scleroderma, systemic sclerosis, retroperitonealfibrosis, prevention of keloid formation, or cirrhosis.
 12. A compound,comprising any one of the following: